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Molecular Basis of Disease > Autoinflammatory diseases > Flashcards

Autoinflammatory diseases Flashcards

1
Q

What leads to the production of inflammatory cytokines?

A

Infection

Tissue damage

Environmental stress

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2
Q

What differentiates autoimmune from autoinflammatory conditions?

A

They lie on opposite ends of the same spectrum

Result due to opposite mechanisms

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3
Q

What is overactive in autoinflammatory conditions?

A

The innate immune system

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4
Q

What is overactive in autoimmune conditions?

A

The adaptive immune system

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5
Q

What are the different classes of autoinflammatory and autoimmune conditions?

A

Polygenic

Monogenic

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6
Q

What is a polygenic condition?

A

Many genes are responsible for the pathology

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7
Q

What is a monogenic condition?

A

One gene is responsible for the pathology

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8
Q

Examples of rare monogenic autoinflammatory diseases

A

CAPS

FMF

TRAPS

PAPA

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9
Q

Examples of polygenic autoinflammatory diseases

A

Still’s

Chron’s

Ulcerative colitis

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10
Q

Examples of mixed pattern diseases

A

Reactive psoriasis arthritis

Ankylosing spondylitis

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11
Q

Examples of classic polygenic autoimmune diseases

A

Rheumatoid arthritis

SLE

Type 1 diabetes

Sjorgen’s syndrome

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12
Q

What is a central mediator of symptoms and signs in autoinflammatory syndromes?

A

IL-1b

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13
Q

What is the death domain superfamily?

A

Member of the innate immune system

Play pivotal roles in apoptosis and inflammation

Group of highly conserved and closely related proteins

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14
Q

How many death domains are there in the death domain superfamily?

A

39

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15
Q

How many death effector domains are there in the death domain superfamily?

A

8

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16
Q

How many caspase recruitment domains are there in the death domain superfamily?

A

33

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17
Q

How many pyrin domains are there in the death domain superfamily?

A

22

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18
Q

Describe the shape of death domains

A

6 a-helices arranged in antiparallel bundle

Homotypic protein protein interactions

No cross interactions between families

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19
Q

What are the characteristics of autoinflammatory conditions?

A

No class II HLA-association

No gender predisposition

No auto-antibodies

No antigen-specific T cells

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20
Q

How have autoinflammatory diseases been beneficial to the scientific community?

A

Allowed us to understand the mechanisms regulating inflammation

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21
Q

Give an example of an autoinflammatory condition that has helped us understand the mechanisms regulating inflammation

A

CAPS

Shed light on the role of the NLRP3 inflammasome

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22
Q

What are the symptoms of autoinflammatory syndromes?

A

Fever

Serositis

Arthritis

Rash

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23
Q

What are common genetic links in autoinflammatory conditions?

A

Inherited or acquired

Inherited forms usually manifest early

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24
Q

What are the common mechanisms that are faulty in autoinflammatory conditions?

A

Cytokine dysregulation

Abnormal protostasis

ER and mitochondrial stress

Autophagy

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25
Q

What criteria must a patient follow in order to be diagnosed with an inflammatory condition?

A

Recurrent or continuous symptoms

Family history

Exclusion of other causes

Elevated acute phase response proteins

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26
Q

What is CAPS?

A

Range of conditions caused by the same gene mutation

But presents differently

Caused by mutations in the NLRP3 on chromosome 1

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27
Q

What are the three conditions caused by mutations in the NLRP3 gene?

A

Familial cold urticaria

Muckle Wells Syndrome

NOMID/CINCA

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28
Q

What is the genetic link of Familial cold urticaria?

A

Autosomal dominant

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29
Q

What is the genetic link of Muckle Wells syndrome?

A

Autosomal dominant

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30
Q

What is the genetic link of NOMID/ CINCA?

A

Sporadic

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31
Q

What are the symptoms of Familial Cold Urticaria?

A

Cold induced rash

Arthralgia

Conjunctivitis

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32
Q

What are the symptoms of Muckle Wells syndrome?

A

Sensorineural deafness

AA amyloidosis

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33
Q

What are the symptoms of NOMID/CINCA?

A

Progressive chronic meningitis

Destructive arthritis

34
Q

What is the severity of Familial cold urticaria?

A

Mild

Only presents in the cold

35
Q

What is the severity of Muckle wells syndrome?

A

Moderate

36
Q

What is the severity of NOMID/CINCA?

A

Very severe

Sufferers die in childhood

37
Q

What are the day-to-day symptoms of CAPS?

A

Widespread uritcarial rash

Flu-like symptoms

Anaemia

Headaches

Fatigue

Depression

38
Q

What are the long-term symptoms of CAPS?

A

Neurological damage

Sensorineural deafness

Visual loss

Cognitive impairment

AA amyloidosis

39
Q

What activates the NLRP3 inflammasome?

A

Potassium efflux induced by bacterial proteins or extracellular ATP which interacts with K+ channels

DAMPs or PAMPs forming phagolysosomal vessels

Transcription of proinflammatory cytokines

40
Q

What type of molecule is NLRP3?

A

NOD

41
Q

What are NODs?

A

As supposed to TLRs, they are cytosolic receptors

42
Q

Consequences of NLRP3 activation

A

Amplifies the immune response

Causes apoptosis

43
Q

How does NLRP3 detect PAMPs or DAMPs?

A

Through leucine rich repeats

44
Q

How does the NLRP3 amplify the immune response?

A

Initiates caspase-1 self-cleavage and forms active caspase-1

45
Q

How does caspase-1 cause the effects on the inflammatory system?

A

Stimulates cleavage of pro-IL1b into activated IL-1b

46
Q

How do mutations to the NLRP3 cause autoinflammatory conditions?

A

Leads to constitutive overactivation of caspase 1

Leads to spontaneous formation of the IL-1 inflammasome

Continuous production of IL-1b

47
Q

Which targets does IL-1b affect?

A

Brain

Bone

Endothelial cells

48
Q

How does IL-1b affect the brain?

A

On the hypothalamus

Induces fever and pain sensitisation

49
Q

How does IL-1b affect bones?

A

Bone resorption

Cartilage breakdown

Production and enhanced activation of immune cells

Causes the release of inflammatory molecules

50
Q

How does IL-1b affect endothelial cells?

A

Releases IL-6

Causes the production and release of acute phase response proteins from the liver

51
Q

What is the correlation between IL-1b concentration and CAPS presentation?

A

The higher the IL-1b concentration in the blood, the more severe the presentation of the disease

52
Q

What are treatments of CAPS?

A

IL-1 blockade

Caspase 1 inhibition

IL-1b receptor blockade

53
Q

What was the result of IL-1 blockade as a treatment for CAPS?

A

Reduced levels of IL-1b

Without decreasing it too much below physiological levels

54
Q

What was the result of caspase 1 inhibition?

A

Lowering IL-1b concentration was made possible, but a high amount needed to make a small change

Caspase-1 is important in other processes

Moderately reduced serum cytokine concentration

55
Q

What is Anakinra?

A

A drug used for CAPS that blocks the IL-1 receptor

Prevents IL-1b from binding

And so prevents IL-1 from working intracellulary

56
Q

What is the half-life of Anakinra?

A

4-6 hours

57
Q

What was the effect of Anakinra in CAPS patients?

A

Affected individuals developed normal kidney function and went from infertile to fertile because of the drug

58
Q

Where is Anakinra derived from?

A

Recombinant form of endogenous IL-1Ra

59
Q

What were the limitations of Anakinra?

A

Difficult to obtain funding for the expensive drug

Daily sometimes painful injections required

Injection site reactions

Inconvenient - needs to be stored between 2-8 degrees, repeated dosing within 24 hr is crucial

Major rebound flares

Infectious risks

60
Q

What are the advantages of Anakinra?

A

Short half-life meant it was safe since it was cleared out in the urine within a few hours

CAPS sufferers were sensitive to IL-1 receptor blockade when all other therapies were unsuccessful

61
Q

Why was CAPS a good disease to test novel therapies?

A

IL-1 was thought to play a major role in many acquired diseases

CAPS is a disease with very clear parameters

62
Q

Why is CAPS a condition with clear parameters?

A

Patients have defined, clear symptoms

There is a genetic test for the condition

Blood test results correlated with the level of disease in the patient

63
Q

What was found to be a good alternative drug to Anakinra?

A

Canakinumab

64
Q

Why was Canakinumab a better alternative than Anakinra?

A

Fully human IgG cap antibody targeted against IL-1b

Showed rapid improvement of symptoms within hours

Levels of biomarkers lowered to normal and maintained for 115 days after one dose

65
Q

What is the safety profile of Canakinumab?

A

Well-tolerated

Few infection-site reactions

No evidence for development of antibodies or immunogenicity

66
Q

What conditions are similar to CAPS?

A

Familial Mediterranean Fever

TRAPS

DIRA

DITRA

MKD

67
Q

What is FMF?

A

Familial Mediterranean Fever

Commonest genetic disease in the East Mediterranean

68
Q

What are the symptoms of FMF?

A

Recurrent, self-limiting episodes of fever, peritonitic pain, pleurtic pain and arthritis

Lasts 48-72 hours

69
Q

What gene defect leads to FMF?

A

Mutation in the MEFV gene

70
Q

How does the mutation of MEFV lead to FMF?

A

MEFV gene codes for the pyrin protein

This is a gain of function mutation

Causes overactivation of caspase-1 and more IL-1b to become released

71
Q

Do FMF patients have increased or decreased chances of developing infections?

A

Decreased

These patients have lower infection rates because of the increased IL-1b release

72
Q

What is pyrin?

A

A component of the inflammasome

73
Q

What is the function of pyrin?

A

Activates caspase-1 by autoproteolysis

Indirect sensor of many bacterial toxins through their effects on actin

74
Q

What is colchicine?

A

An effective prophylaxis to FMF

Root found naturally

75
Q

Why is colchicine effective in FMF if it has a low therapeutic index?

A

It concentrates in neutrophils

Because they lack the P-glycoprotein efflux pump that removes it from the inside of the cell

76
Q

How does colchicine effectively treat FMF?

A

Competes with cleaving of NF-kB

Decreases the concentration of NFkB in the blood

77
Q

How does colchicine cause effects on the cells it targets?

A

Binds to tubulin to arrest microtubule polymerization

Inhibits neutrophil chemotxis

Suppresses NF-kB activation

Reduces levels of inflammatory cytokines

78
Q

What is the mortality of FMF patients?

A

Comparable to normal population

AA amyloidosis causes death in the undiagnosed population

79
Q

What are the reproductive outcomes of FMF patients?

A

Comparable to the normal population

Colchicine does not have effects on fertility

80
Q

What are the incidences of colchicine resistance in FMF patients?

A

Rare

IL-1 agents are used in such case

Molecular Basis of Disease (28 decks)

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